Accession	GSE245832
Status	2024/9/12
Title	DNA methylation profiling identifies TBKBP1 as potent amplifier of cytotoxic activity in CMV-specific human CD8+ T cells
Organism	Homo sapiens
Experiment type	Methylation profiling by high throughput sequencing
Summary	Epigenetic mechanisms stabilize gene expression patterns during CD8+ T cell differentiation. Although adoptive transfer of virus-specific T cells is clinically applied to reduce the risk of virus infection or reactivation in immunocompromised individuals, the DNA methylation pattern of virus-specific CD8+ T cells is largely unknown. Hence, we here performed whole-genome bisulfite sequencing of cytomegalovirus-specific human CD8+ T cells and found that they display a unique DNA methylation pattern consisting of 79 differentially methylated regions (DMRs) when compared to memory CD8+ T cells. Among the top demethylated DMRs in cytomegalovirus-specific CD8+ T cells was TBKBP1, coding for TBK-binding protein 1 that can interact with TANK-binding kinase 1 (TBK1) and mediate pro-inflammatory responses in innate immune cells downstream of intracellular virus sensing. Since TBKBP1 has not yet been reported in T cells, we aimed to unravel its role in virus-specific CD8+ T cells. TBKBP1 demethylation in terminal effector CD8+ T cells correlated with higher TBKBP1 expression at both mRNA and protein level, independent of alternative splicing of TBKBP1 transcripts. Notably, the distinct DNA methylation patterns in CD8+ T cell subsets was stable upon long-term in vitro culture. TBKBP1 overexpression resulted in enhanced TBK1 phosphorylation upon stimulation of CD8+ T cells and significantly improved their virus neutralization capacity. Collectively, our data demonstrate that TBKBP1 modulates virus-specific CD8+ T cell responses and could be exploited as therapeutic target to improve adoptive T cell therapies.
Samples	GSM ID Sample info Characteristics Description GSM7849753 #1 naive CD8+ T cells, blood, 4 hour stimulation donor:#1; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7+/CD28_int/KLRG1-/CX3CR1-/CD45RA_high; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849754 #1 memory CD8+ T cells, blood, 4 hour stimulation donor:#1; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7-/CD28_high/CD27+/CD45RA-; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849755 #1 CMV-specific CD8+ T cells, blood, 4 hour stimulation donor:#1; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/IFNgamma+; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849756 #2 naive CD8+ T cells, blood, 4 hour stimulation donor:#2; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7+/CD28_int/KLRG1-/CX3CR1-/CD45RA_high; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849757 #2 memory CD8+ T cells, blood, 4 hour stimulation donor:#2; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7-/CD28_high/CD27+/CD45RA-; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849758 #2 CMV-specific CD8+ T cells, blood, 4 hour stimulation donor:#2; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/IFNgamma+; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849759 #3 naive CD8+ T cells, blood, 4 hour stimulation donor:#3; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7+/CD28_int/KLRG1-/CX3CR1-/CD45RA_high; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849760 #3 memory CD8+ T cells, blood, 4 hour stimulation donor:#3; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7-/CD28_high/CD27+/CD45RA-; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849761 #3 CMV-specific CD8+ T cells, blood, 4 hour stimulation donor:#3; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/IFNgamma+; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849762 #4 naive CD8+ T cells, blood, 4 hour stimulation donor:#4; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7+/CD28_int/KLRG1-/CX3CR1-/CD45RA_high; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849763 #4 memory CD8+ T cells, blood, 4 hour stimulation donor:#4; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7-/CD28_high/CD27+/CD45RA-; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849764 #4 CMV-specific CD8+ T cells, blood, 4 hour stimulation donor:#4; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/IFNgamma+; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849765 #5 memory CD8+ T cells, blood, 4 hour stimulation donor:#5; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/CCR7-/CD28_high/CD27+/CD45RA-; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool - GSM7849766 #5 CMV-specific CD8+ T cells, blood, 4 hour stimulation donor:#5; serotype:CMV positiv; tissue:peripheral blood; cell type:CD8 T cell; marker:CD3+/CD4-/CD8+/IFNgamma+; treatment:4 hour stimulation with CMVpp65 overlapping peptide pool -
Platform	GPL24676  : Illumina NovaSeq 6000 (Homo sapiens)
Literature	39325839